Pharmacokinetics, safety, and tolerability of the 2- and 3-direct-acting antiviral combination of AL-335, odalasvir, and simeprevir in healthy subjects

Abstract

This Phase I, open-label, two-group, fixed-sequence study evaluated the pharmacokinetics and safety of AL-335, odalasvir, and simeprevir in healthy subjects. Group 1 (n = 16) received AL-335 800 mg once daily (QD) (days 1-3, 11-13, and 21-23), simeprevir 150 mg QD (days 4-23), and odalasvir 150 mg (day 14) followed by 50 mg QD (days 15-23). Group 2 (n = 16) received the same AL-335 regimen as in Group 1 plus odalasvir 150 mg (day 4) followed by 50 mg QD (days 5-23) and simeprevir 150 mg QD (days 14-23). Blood samples were collected to determine plasma concentrations of AL-335 (prodrug) and its metabolites, ALS-022399 (monophosphate precursor) and ALS-022227 (parent nucleoside), odalasvir, and simeprevir. Thirty-two subjects were enrolled. Odalasvir and simeprevir given alone, or in combination, increased AL-335 area under plasma concentration-time curve over 24 hours (AUC _{0-24 h}) 3-, 4-, and 7- to 8-fold, respectively; ALS-022399 AUC _{0-24 h} increased 2-, 2-, and 3-fold, respectively. Simeprevir had no effect on ALS-022227 AUC _{0-24 h}, whereas odalasvir with/without simeprevir increased ALS-022227 AUC _{0-24 h} 1.5-fold. AL-335 had no effect on odalasvir or simeprevir pharmacokinetics. Odalasvir and simeprevir AUC _{0-24 h} increased 1.5- to 2-fold for both drugs when coadministered irrespective of AL-335 coadministration. Study medications were well tolerated with no serious adverse events. One subject prematurely discontinued study drugs (unrelated event). This study defined the preliminary pharmacokinetic and safety profiles of the combination of AL-335, odalasvir, and simeprevir in healthy subjects. These data support the further evaluation of this combination for the treatment of chronic hepatitis C virus infection.

Trial registration: ClinicalTrials.gov NCT02512562.

Keywords: AL‐335; drug safety; drug‐drug interactions; hepatitis C virus; odalasvir; pharmacokinetics; simeprevir.

Figure 1

Study design. PK pharmacokinetics

Figure 2

Subject disposition. PK pharmacokinetic; QD once daily; TEAE treatment‐emergent adverse event. ^aRisk of interaction between treatment for tooth abscess and study drugs. ^bThe subject that withdrew from the study on day 2, for reasons not related to the study, received two QD administrations of AL‐335 800 mg alone (day 1 and day 2) before any PK samples were taken and was therefore excluded from the PK analysis

Figure 3

Mean (±SD ) plasma concentration‐time curve of (A) AL‐335; (B) ALS‐022399; (C) ALS‐022227; (D) simeprevir; and (E) odalasvir by group^a. ODV, odalasvir; QD, once daily; SMV, simeprevir. ^aGroup 1 received SMV 150 mg QD on days 4‐23, ODV 150 mg (loading dose) on day 14, ODV 50 mg QD on days 15‐23, and AL‐335 800 mg QD on days 1‐3, 11‐13, and 21‐23. Group 2 received ODV 150 mg (loading dose) on day 4, ODV 50 mg QD on days 5‐23, SMV 150 mg QD on days 14‐23, and AL‐335 800 mg QD on days 1‐3, 11‐13, and 21‐23